Эффективность и безопасность селелексора в сочетании с VRD в недавно диагностированном миеломе с EMD: фазы 2 суд.

Introduction

Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells in the bone marrow, which leads to the production of monoclonal immunoglobulins and associated clinical manifestations such as bone lesions, anemia, renal impairment, and hypercalcemia. Extramedullary disease (EMD) represents an aggressive subtype of MM that occurs in ∼7% to 18% of newly diagnosed cases and up to 20% to 30% of relapsed/refractory (R/R) patients 1 in whom malignant plasma cells infiltrate soft tissues or organs outside the bone marrow, such as the skin, liver, lymph nodes, or central nervous system. 2 EMD is associated with a poor prognosis, high-risk cytogenetics (del[17p], t[4;14], gain[1q]), 3 and resistance to conventional therapies, with a median overall survival (OS) often <12 months in relapsed settings. 4 The pathogenesis of EMD involves enhanced plasma cell migration and adhesion driven by dysregulation of exportin 1 (XPO1)–mediated nuclear export, proteasome activity, immunomodulatory pathways, and glucocorticoid signaling. 5 , 6

Responses in EMD, including bone-related disease, are suboptimal because of rapid disease progression and extramedullary involvement. Conventional therapies, such as proteasome inhibitors, immunomodulatory drugs, and corticosteroids, show reduced efficacy in EMD because of its aggressive biology and resistance mechanisms. 1 , 7 , 8 Selinexor, a selective inhibitor of nuclear export by targeting XPO1, has demonstrated efficacy in R/R MM by inducing nuclear retention of tumor suppressor proteins and apoptosis in myeloma cells. Approved by the US Food and Drug Administration for penta-refractory MM, selinexor has shown promise in combination regimens, such as in the STORM and BOSTON trials, in which selinexor (S) plus bortezomib (V) and dexamethasone (D) improved progression-free survival (PFS) compared with VD alone. 5 , 9 However, data on selinexor-based quadruplet therapy, including with lenalidomide (R), remain limited, particularly in EMD cohorts.

The SVRD regimen, in which S, V, R, and D are combined, represents a novel quadruplet approach that leverages synergistic mechanisms; XPO1 inhibition to block nuclear export, proteasome inhibition to disrupt protein degradation, immunomodulatory drug–mediated cereblon-dependent ubiquitination of transcription factors, and the anti-inflammatory effects of dexamethasone. Preclinical studies suggest that the antimyeloma activity is enhanced with this combination, which potentially overcomes EMD resistance by targeting multiple pathways. 10 Case series have reported overall response rates (ORRs) in excess of 60% in R/R MM with EMD, thus warranting further investigation. 11 , 12

Methods

Study design

This was a multicenter, open-label, single-arm, exploratory phase 2, investigator-initiated trial that was designed to evaluate the safety and efficacy of SVRD in patients with newly diagnosed MM (NDMM) who presented with EMD. The study was conducted at 2 centers in China from 17 October 2022 to 27 November 2025. The study was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants before enrollment.

Patients

Eligible patients were adults aged 18 to <75 years with NDMM, diagnosed according to International Myeloma Working Group (IMWG) criteria, and confirmed EMD, defined as diffuse organ infiltration without focal lesions but with measurable paraosseous or bone-independent visceral/soft tissue disease with a diameter of ≥2 cm confirmed by biopsy or imaging (positron emission tomograpy–computed tomography [PET-CT], magnetic resonance imaging [MRI], or CT). In all cases, at least 1 EMD site was confirmed for each patient from a biopsy; in patients with multiple EMD sites, the remaining lesions were diagnosed as EMD based on imaging findings. Patients with grade 2 or higher peripheral neuropathy or neuralgia, plasma cell leukemia, serious thrombotic events, and a creatinine clearance rate of <30 mL/min were excluded.

Treatment

Enrolled patients received 4 cycles of SVRD induction therapy (28 days per cycle), comprising 60 mg S orally once weekly on days 1, 8, 15, and 22, administered with antiemetic prophylaxis; 1.3 mg/m 2 V subcutaneously on days 1, 8, 15, and 22; 25 mg R orally on days 1 to 14 with dose adjustments for renal function; and 20 mg D orally on days 1, 2, 8, 9, 15, 16, 22, and 23 (reduced to 10 mg for patients >75 years and those with comorbidities). Following induction, patients who were eligible for autologous stem cell transplantation (ASCT) underwent conditioning with high-dose melphalan, followed by ASCT. Following the transplantation, these patients received 2 cycles of VRD consolidation (1.3 mg/m 2 V subcutaneously on days 1, 8, 15, 22; 25 mg R on days 1-21; and 20 mg D on days 1-2, 8-9, 15-16, 22-23). Patients who were ineligible for or declined ASCT received another 4 cycles of SVRD consolidation at the induction doses with a reduction of S to 40 mg for grade >2 nonhematologic toxicities. Maintenance therapy consisted of V (1.3 mg/m 2 subcutaneously every 2 weeks) and R (10 mg on days 1-21) for at least 24 months or until disease progression, unacceptable toxicity, or patient withdrawal.

End points and assessments

The primary end point was the best ORR during induction, defined according to the IMWG criteria. ORR during induction was defined as the proportion of patients who achieved partial response (PR) or better according to the IMWG criteria at any time from the first dose through the end of induction; patients without any postbaseline response assessment during induction were considered nonresponders. Responses achieved before early discontinuation or transition to subsequent therapy were included in the best overall response. Patients who lacked EMD restaging were not evaluable for overall response and were imputed as nonresponders in the modified intention-to-treat (mITT) ORR analysis; hematologic responses were reported separately. Secondary end points included imaging-based responses of EMD lesions, PFS, OS, and safety. Disease-specific assessments were conducted at baseline, on day 1 of each induction cycle, after consolidation, every 3 months during maintenance, and at disease progression or suspected response. Minimal residual disease (MRD) was evaluated in patients who achieved complete response (CR) or stringent CR (sCR). Imaging (PET-CT, MRI, or CT) was used to assess EMD lesions (≥2 cm) at baseline, after induction, after consolidation, every year during maintenance, and at progression, with responses categorized as complete resolution (disappearance of lesions), partial reduction (≥50% size decrease), stable disease, or progressive disease. If patients were evaluated using PET-CT, the criteria of the EANM (European Association of Nuclear Medicine) guideline were followed. 13 High-risk cytogenetic abnormalities were assessed at baseline using Mayo Stratification for Myeloma and Risk-Adapted Therapy (mSMART) 3.0.

Safety was assessed by evaluating patient history, physical examinations, and laboratory assessments, and adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (version 4.03).

Statistical analysis

The mITT population, comprising all enrolled patients who met the eligibility criteria and received at least 1 dose of SVRD, was used for the primary efficacy analysis. The safety population included all patients who received at least 1 dose of the study drug.

In the primary analysis, the ORR was estimated using a 2-sided exact 95% confidence interval (CI) Clopper-Pearson method, and statistical significance was declared if the lower CI boundary exceeded 40%. Secondary endpoints were similarly analyzed using 95% CIs. The PFS (time from treatment initiation to progression or death) and OS (time from treatment initiation to death) were summarized using Kaplan-Meier methods. Safety outcomes were summarized using frequencies and 95% CIs for AEs. All statistical analyses were performed using SPSS, and 2-sided P values <.05 were considered significant.

Results

Patients

From October 2022 to November 2025, 30 patients with NDMM and confirmed EMD were enrolled in 2 hospitals in China. One patient was excluded from the efficacy analysis (for withdrawal before dosing), leaving 29 evaluable patients in the mITT and safety populations. The median age was 60 years (range, 43-75), with 16 (55.2%) males and 13 (44.8%) females. EMD was confined to paraskeletal plasmacytomas in 23 patients (79.3%), involved both paraskeletal and extraosseous sites in 5 (17.2%) patients, and presented as only extraosseous disease in 1 (3.4%) patient. The specific EMD sites included paraskeletal plasmacytomas (96.6%), lymph nodes (10.3%), pleura (10.3%), and muscles (3.4%). Cytogenetic abnormalities were assessed using fluorescence in situ hybridization on bone marrow aspirates at baseline, and high-risk features were defined according to the mSMART 3.0 criteria (del[17p], t[4;14], t[14;16], or gain[1q]). Among the 29 patients, 17 (58.6%) had at least 1 high-risk abnormality, including 6 with gain(1q) and t(4;14) double positivity, 7 with only gain(1q), 1 with only del(17p), 1 with gain(1q) and del(17p) double positivity, and 1 with gain(1q), t(4;14), and del(17p) triple positivity; 1 patient with a 1p deletion was not classified as high risk because a 1p deletion is not included in the mSMART 3.0 criteria. Cytogenetic data were unavailable for 3 (10.3%) patients. Most patients (24; 82.8%) had normal lactate dehydrogenase levels, whereas 5 (17.2%) had elevated levels. The creatinine clearance rates varied; 10 (34.5%) patients had rates in excess of 90 mL/min, 11 (37.9%) had rates of 60 to 90 mL/min, and 8 (27.6%) had rates of 30 to 60 mL/min. The baseline characteristics are summarized in Table 1 .

Treatment exposure

Patients received a median of 4 cycles of SVRD (range, 1-8) during induction and consolidation. At the data cutoff, 27 (93.1%) patients completed at least 4 cycles of SVRD. Fifteen patients (51.7%) proceeded to ASCT with high-dose melphalan conditioning. A total of 7 (24.1%) patients completed or were completing 4 cycles of SVRD consolidation but did not undergo ASCT because of ineligibility or patient refusal, and 1 patient did not proceed to ASCT because of progressive disease (PD). Two patients withdrew from the study for personal reasons, and 1 patient was lost to follow-up after 1 cycle of SVRD. In addition, 2 patients underwent chimeric antigen receptor T-cell therapy because of disease progression or personal preference. At the time of reporting, 2 patients were still being evaluated for or were awaiting ASCT. At the time of writing, 13 patients were undergoing maintenance therapy. Of those, 11 (84.6%) were receiving V and R with a median treatment duration of 10 months (range, 1-25). Two additional patients received V and thalidomide to manage persistent low platelet counts. S dose reductions occurred in 10 patients (34.5%; nausea, n = 2; thrombocytopenia, n = 8; pneumonia, n = 1). The protocol treatment was discontinued in 10 (34.5%) patients because of disease progression (n = 6), patient choice (n = 3), or loss to follow-up (n = 1).

Efficacy

In the mITT population (n = 29), the best ORR during induction was 89.7% with 17 sCRs (58.6%), 1 CR (3.4%), 3 very good PRs (VGPR; 10.3%), and 5 PRs (17.2%). Stable disease occurred in 1 patient who discontinued after 4 induction cycles and declined further evaluation. One patient achieved serologic VGPR without evaluable imaging and discontinued after 4 cycles and declined further assessment. One patient was lost to follow-up after 1 month of treatment. The responses for individual patients are shown in Figure 1 .

Imaging (PET-CT, MRI, or CT) was performed for all 29 patients with EMD. In total, 28 had measurable EMD (≥2 cm), and 1 had nonmeasurable EMD (pleural effusion). In total, 27 patients underwent baseline PET-CT imaging. A regression of EMD lesions was observed in 26 (89.7%) patients, with complete resolution in 23 (79.3%) and partial reduction in 3 (10.3%; defined as a PET/CT Deauville score ≤3 or ≥50% or size decrease on CT or MRI if PET/CT was not applicable). A follow-up imaging assessment was not evaluable for 3 patients because of refusal or loss to follow-up.

The median PFS was not reached with a 12-month PFS rate of 87.9% (95% CI, 68.4-96.6). The median OS was not reached at a median follow-up of 18 months (range, 1-37), and the 12-month OS rate was 96.3% (95% CI, 78.4-99.5).

We performed an exploratory analysis of the response rates among the 5 patients with combined paraskeletal and extraosseous EMD (patient 5, 6, 8, 13, and 21) and the 1 patient with only extraosseous EMD (patient 18). Among the 6 patients with extraosseous EMD, 5 completed all 4 cycles of induction; patient 13 experienced PD after 3 cycles (both serologic and extramedullary PD) and ultimately died at 8 months. Of the 5 patients who completed induction, 2 achieved sCR (patient 5 and 21), 1 achieved CR (patient 18), 1 achieved VGPR (patient 8), and 1 achieved PR (patient 6). PET-CT imaging confirmed the complete resolution of EMD lesions in 4 of the 5 completing patients and partial reduction in 1 patient (patient 6) who later developed serologic and extramedullary PD after stem cell collection whereas awaiting ASCT. Overall, the ORR (PR or better) after induction was 83.3% (5/6) in the extraosseous subgroup. The median PFS was 14 months and the median OS was not reached. The 12-month PFS rate was 66.7% and the 12-month OS rate was 83.3%.

Safety

When excluding the patient who was lost to follow-up after 1 cycle, 28 patients in the safety population experienced at least 1 treatment-emergent AE (TEAE). Common TEAEs (any grade, incidence ≥20%) during the induction cycle included thrombocytopenia (44.8%), neutropenia (51.7%), decreased appetite (31.0%), and elevated liver enzymes (31.0%). Grade 3 or 4 TEAEs occurred in 11 patients (37.3%), including thrombocytopenia (24.1%), neutropenia (6.9%), pneumonia (10.3%), elevated liver enzymes (3.4%), and deep vein embolism (6.9%). No treatment-related deaths were reported. The AEs are summarized in Table 2 . To emphasize, 3 patients experienced grade 3/4 neutropenia, all of whom were managed with granulocyte colony-stimulating factor (G-CSF) for secondary prophylaxis at the investigator’s discretion. G-CSF was administered at a total of 6 short-acting doses (300 μg subcutaneously per dose) across 2 patients and as 1 long-acting dose (pegylated recombinant human G-CSF) in the third patient with limited duration as follows: 1 patient received 1 short-acting dose in cycle 4; 1 patient received 2 consecutive short-acting doses in cycle 3; and 1 patient received 1 short-acting dose in cycle 1, followed by 2 consecutive short-acting doses in cycle 2, and 1 PEG-rhG-CSF (pegylated recombinant human granulocyte colony-stimulating factor) dose in cycle 3. Seven patients experienced grade 3/4 thrombocytopenia, 4 of whom were managed with thrombopoietin (TPO) receptor agonists as secondary prophylaxis at the investigator’s discretion. TPO support was limited in duration and included 2 consecutive doses of TPO in cycle 3 for 2 patients, 25 mg oral hetrombopag twice daily for 2 weeks in cycle 3 for 1 patient, and romiplostim (1 dose subcutaneously in cycle 3) for 1 patient. The remaining 3 patients did not receive TPO or oral TPO agonists during S therapy; thrombocytopenia occurred in cycle 4 in 2 of these patients and in cycle 3 in another. Other supportive care, including antiemetics, antiviral prophylaxis (acyclovir), and IV fluids, effectively mitigated most toxicities.

Discussion

This study demonstrated that the SVRD regimen yields promising early efficacy in patients with NDMM and EMD, a subgroup that has historically been associated with aggressive disease biology and inferior outcomes. In our cohort of 29 evaluable patients who predominantly had paraskeletal plasmacytomas (79.3%), the best ORR reached 89.7%, including sCR in 58.6%. Notably, extramedullary lesion regression was observed in 89.7% of patients with complete resolution in 79.3%, alongside a 12-month PFS rate of 87.9% and a 12-month OS rate of 96.3%. These results suggest that SVRD induces deep and durable responses, even in the context of high-risk cytogenetics, including ultra–high-risk (double-hit) features in 27.6% of patients, and supports progression to ASCT in nearly half of patients.

EMD at diagnosis portends a dismal prognosis in patients with NDMM, with a median PFS typically ranging from 5.1 to 11.1 months and an OS from 14.8 to 26.9 months, which is substantially worse than patients without EMD. 14 , 15 However, outcomes vary markedly by EMD subtype; paraskeletal involvement, which comprised the majority of our cases, is associated with superior survival (median OS, 44-45 months) when compared with extraosseous plasmacytomas (median OS, 20 months). 16 In our cohort, patients with paraskeletal EMD (n = 24) had a median PFS that was not reached and a 12-month PFS rate of 93.8%; the median OS was not reached and the 12-month OS was 100%. In contrast, the extraosseous subgroup (n = 6) showed a median PFS of 14 months and a median OS that was not reached, with 12-month PFS and OS rates of 66.7% and 83.3%, respectively. These findings underscore the markedly worse prognosis in extraosseous EMD compared with paraskeletal involvement, consistent with previous reports of rapid progression and inferior survival in hematogenous spread. The enrichment in paraskeletal disease in our cohort likely contributed to the favorable PFS and OS observed, although the inclusion of mixed paraskeletal/extraosseous and only extraosseous cases tempered direct extrapolation to purely extraosseous cohorts in which responses are often shallower and relapses more rapid. 17 Nonetheless, the 79.3% complete EMD resolution rate exceeded historic benchmarks for lesion regression in mixed EMD populations (typically 30%-50% with standard triplet induction), 18 highlighting SVRD’s potential to target extramedullary niches through S’s nuclear export inhibition, which disrupts oncogenic signaling in plasma cells that are less reliant on bone marrow microenvironment support.

Comparisons with contemporary NDMM regimens underscore SVRD’s competitive profile in EMD. Standard V-based triplets, like VRD, achieved ORRs of 93.8% in transplant-eligible NDMM overall and ≥CR rates of 70.1%, but EMD-specific subsets achieved lower deep responses (CR rates, ∼35%-50%) and median PFS rates of 16 to 25 months. 17 , 19 The addition of daratumumab to VRD (D-VRD) in the PERSEUS trial (ClinicalTrials.gov identifier: NCT03710603 ) enhanced the MRD negativity and PFS (48-month rate, 84.3%) in broad NDMM populations, with the ORR nearing 96.6% and ≥CR reaching 87.9%. 19 , 20 However, EMD-enriched analyses remain limited, and extraosseous-predominant studies show attenuated benefits (ORR, ∼58%; median PFS, 5 months). 15 SVRD’s ORR (89.7%) and sCR rate (58.6%) align closely with these, whereas the 87.9% 12-month PFS (median not reached) surpasses historic benchmarks in EMD cohorts treated with VRD alone (estimated 12-month PFS ∼60%-70%) or even that of quadruplet therapy in high-risk subsets. 19 This may reflect S’s synergistic role in overcoming EMD resistance, as evidenced by early phase data showing deep responses in EMD/HR (high-risk) NDMM. Previously, a smaller, single-arm observational study of SVRD in 10 patients with NDMM-EMD (median age, 62 years; 50% cortical bone involvement; only 30% high-risk cytogenetics; only 3 high-risk cases; and 2 harboring only 1q21+) reported a 100% ORR (sCR/CR, 40%; VGPR, 40%; PR, 20%) and 100% EMD response (40% complete resolution; 60% shrinkage, including rapid reductions in central nervous system and chest soft tissue lesions), alongside a 12-month PFS of 60% and 12-month OS of 90% (medians not reached at the median follow-up of 15 months). In contrast, our larger series (n = 29) with deeper complete resolutions (79.3%), superior early PFS (87.9%), and a higher burden of ultra–high-risk features (eg, 27.6% double-hit abnormalities) further illustrates SVRD’s potential as a quadruplet induction strategy for this aggressive subgroup. 21 Although the smaller sample size and inclusion of more diverse extraosseous sites (eg, central nervous system, kidney, sinus) may contribute to the lower PFS in the previous study compared with our paraskeletal-enriched cohort, both studies demonstrated SVRD’s ability to achieve high rates of EMD clearance (our 79.3% vs their 40% complete resolution) and deep remissions. Only 20% proceeded to ASCT in their series vs 51.7% in ours, suggesting SVRD’s efficacy as an induction bridge even in challenging extraosseous cases. Caution is warranted in extraosseous-only comparisons, because such lesions exhibit heightened aggressiveness and lower response durability across regimens.

The safety profile of SVRD was consistent with known class effects, with no treatment-related deaths and grade 3/4 events occurring in only 37.3% of patients, primarily cytopenias. Thrombocytopenia (44.8% any grade; 24.1% grade ≥3) and neutropenia (51.7% any grade; 6.9% grade ≥3) were the most frequent, aligning with rates observed with VRD (thrombocytopenia, 30%-45%; neutropenia, 20%-35%) and D-VRD (similar cytopenia incidence with grade ≥3 neutropenia ∼25%). Nonhematologic toxicities, such as decreased appetite (31.0%) and elevated liver enzymes (31.0%), were mitigated with supportive measures, and dose reductions (34.5%) were infrequent. Compared with immunomodulatory drug/PI (proteasome inhibitor) backbones in EMD, in which cytopenias affect 40% to 60% of patients and infections occur in 20% to 30%, 19 SVRD’s profile seems to be manageable, particularly given the high-risk features and EMD burden. Gastrointestinal effects from S were minimal in this study, possibly because of proactive antiemetics, contrasting with the higher nausea rates (up to 60%) observed in broader S studies.

Limitations of this analysis include the small sample size (n = 29), single-arm design, and relatively short median follow-up (18 months), thereby precluding mature OS estimates. The predominance of paraskeletal EMD may overestimate the efficacy in extraosseous-dominant scenarios, and cytogenetic data gaps (10.3%) limit risk-stratified insights. Larger randomized trials are needed to validate SVRD against D-VRD or novel immunotherapies, like bispecifics/chimeric antigen receptor T-cell therapy, in EMD, especially for ultra–high-risk or extraosseous subsets in which the PFS remains <12 months. In conclusion, SVRD represents a tolerable, efficacious option for NDMM with EMD, offering high EMD clearance and prolonged early PFS that challenge the dismal historic paradigm and warrant broader investigation.

Conclusion

Taken together, SVRD achieved deep hematologic responses, high rates of EMD regression, and promising early survival in a biologically high-risk population. These results support SVRD as a rational frontline option for EMD-positive NDMM, whereas underscoring the need for longer follow-up and randomized, phenotype-stratified studies to validate durability and to compare it against other contemporary regimens, especially in cohorts limited to extraosseous EMD.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Acknowledgment

This work was supported by grants from the National Natural Science Foundation of China (no. 82300234 and 82370205) and the Specialized Diseases Clinical Research Fund of Jiangsu Province Hospital (XB202405).

Authorship

Contribution: Y.J. and L.C. contributed to the concept and design of the study; Y.J., L.C., X.Z., Q.S., Y.Z., J.L., and L.F. performed the research and contributed vital participants; X.C. collected data; X.C. and Y.J. analyzed and interpreted the data; Y.J. wrote the first draft of the manuscript; and all authors approved the final draft of the manuscript and submission of the manuscript.

Footnotes

Data described in the manuscript will not be made publicly available because of participant confidentiality and privacy concerns. Inquiries for data access may be made to the corresponding author, Lijuan Chen ( chenljb@126.com ), upon reasonable request.

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